Neuronal overexcitation is believed to underlie a wide variety of neurological conditions. Seizures are a common manifestation of neuronal overexcitation, and epilepsy is one of the most prevalent neurological conditions. Seizures also occur as a feature of many other neurological diseases. Excitotoxicity, a pathophysiological process characterized by neuronal overexcitation resulting in cellular and/or neuronal network dysfunction or death, is believed to play a role in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, stroke, and other neurological conditions.
Current drugs used to reduce excitotoxicity have been only marginally effective. In addition, use of such drugs is associated with adverse side effects. For example, excitotoxicity drugs can adversely affect normal neuronal function.
Tau is a microtubule-binding protein. Tau becomes hyperphosphorylated and undergoes other posttranslational modifications in Alzheimer's disease, aggregating into neurofibrillary tangles. Tau is a family of six proteins derived from a single gene by alternative mRNA splicing. The human brain tau isoforms range from 352 to 441 amino acids. The tau isoforms contain three or four tubulin binding domains of 31 or 32 amino acids, each in the C-terminal half, and two, one, or no inserts of 29 amino acids each in the N-terminal portion of the molecule. All of the six isoforms have been reported to be present in a hyperphosphorylated state in paired helical filaments associated with tauopathies such as Alzheimer's disease.